Histone deacetylases (HDACs) are a class of enzymes that catalyze the removal of acetyl groups from a lysine residue on both histones and non-histone proteins. The HDAC family of enzymes consists of at least 18 members, which can be subdivided into two categories: the classical HDAC family of zinc-dependent amidohydrolases, including classes I (HDACs 1, 2, 3, and 8), II (HDACs 4, 5, 6, 7, 9, and 10) and IV (HDAC 11); and the NAD+-dependent class III (Sirt 1-7) sirtuin family of HDACs, which are unrelated in sequence and mechanism to classical zinc-dependent HDACs (Li et al., Int. J. Biol. Sci. 2014; 10(7):757-70). HDAC8 is a unique class I HDAC family member because of its reported cytoplasmic and nuclear subcellular localization (as opposed to nuclear localization for other class I HDACs), and its ability to deacetylate non-histone proteins, such as estrogen-related receptor α (ERR-α), and cohesion SMC3 (structural maintenance of chromosome 3) (Olson et al., Chem Biol. 2014; 9(10):2210-6; Balasubramanian et al., Leukemia 2008; 22(5): 1026-34; and Deardorff et al., Nature. 2012; 489 (7415)).
HDACs regulate diverse cellular functions, including gene transcription, cell cycle, apoptosis, growth, differentiation and immunity (Falkenberg et al., Nat. Rev Drug Discov. 2014; 13(9): 673-911; and Li et al., Int. J. Biol. Sci. 2014; 10(7):757-70). HDACs have been found to be associated with multiple human diseases including cancer, inflammatory, immunologic, cardiovascular, and neurodegenerative disorders (Wagner et al. Epigenetics. 2010; 1(3-4):117-136). Deregulation of SMC3 acetylation/acetylation by HDAC8 is associated with Cornelia de Lange syndrome, an inherited congenial malformation disease in which loss of function HDAC8 mutations have recently been identified in a subset of patients (Deardorff et al., Nature. 2012, 13; 489 (7415)). HDAC8 is implicated in multiple human cancers including but not limited to childhood neuroblastoma (Oehme et al., Clin. Cancer Res. 2009; 15(1):91-9), breast cancer (Park at al., Onco.l Rep. 2011; 25(6): 1677-81), hepatocellular carcinoma (Wu et al., Dig Dis. Sci. 2013; 58(12): 3545-53), colon cancer (Kang et al., Cell Death Dis. 2014; 5: e1476), myeloproliferative neoplasms (MPNs) (Gao, et al. Exp Hematol. 2013; 41(3): 261-70.e4), T-cell lymphoma (Balasubramanian et al., Leukemia 2008; 22(5): 1026-34), and AML with inv(16)/t(16;16) (carrying CBFβ-SMMHC fusion protein) (Jing et al., Blood 2014: 124 (21)). HDACs have also been shown to involve in dynamic regulation of inflammatory and anti-inflammatory gene expression, and to influence the functions of various immune cells such as immunosuppressive regulatory T cells (Tregs) and antigen presenting cells (APCs) (Falkenberg et al., Nat Rev Drug Discov. 2014; 13(9): 673-911; and Kroesen et al., Oncotarget. 2014; 5(16): 6558-72). In this regard, HDAC8 has been identified to affect the expression and production of proinflammatory cytokines (e.g. IL-1β; TNFα, IL-6) (16, 17), and to regulate the expression of the MHC class I protein (Li et al., Biochem Biophys Res Commun. 2006; 349(4): 1315-21). Commercially available pan-HDAC inhibitors exhibit significant side effects such as bone marrow depression, diarrhea, weight loss, taste disturbances, electrolyte changes, disordered clotting, fatigue, and cardiac arrhythmias and have narrow therapeutic windows (Witt et al., Cancer Lett. 2009; 277(1):8-21). Accordingly, there is a need in the art for compounds that can selectively modulate the activity of HDAC for the treatment of inflammation and autoimmune diseases as well as applications in cancer immunotherapy.